The regression of atherosclerosis is an important clinical goal, yet it remains largely beyond the reach of the available therapies. In recent studie, we showed that increasing the plasma level of functional HDL particles in Apoe-/- mice, through apoA1 infusion or transgenic means, resulted in rapid plaque regression despite persistent non-HDL hyperlipidemia. Notably, this regression was characterized by reductions in both the number and the inflammatory state of the plaque macrophages (M). Similar results were also found when we treated Ldlr-/- mice with an inhibitor of miR-33, a microRNA that post-transcriptionally represses ABCA1 in the liver and M, thereby reducing HDL biogenesis and reverse cholesterol transport (RCT). Based on these findings, we hypothesize that functional HDL alters M dynamics and inflammatory polarization in the plaque, and that both of these processes are required to effect atherosclerosis regression. Multiple studies have shown that apoA1 recovered from the human artery wall exhibits extensive post-translational modification through oxidative processes, and this affects both the function and distribution (HDL particle association) of apoA1. The overall goal of this proposal is to establish the mechanisms by which apoA1 and HDL stimulate atherosclerosis regression, particularly with regard to the dynamic balance and phenotypic state of M in the plaque, and to determine how these processes may be altered by modified forms of apoA1 of the type that accumulate in human atheroma. We will investigate the bases during atherosclerosis regression for: 1) the reduction in M content, focusing on the kinetic contributions (and their regulation by apoA1/HDL and miR-33) of macrophage retention/chemotaxis, apoptosis/efferocytosis, and proliferation, and of monocyte recruitment (Aim 1); and, 2) the shift in the phenotype of plaque M from the inflammatory M1 to the anti-inflammatory, tissue repair, M2 state (Aim 2). These studies will enhance our understanding of the mechanisms by which functional apoA1/HDL can regress atherosclerosis, whether anti-miR-33 acts by similar or different mechanisms, and how dysfunctional apoA1/HDL affects these mechanisms. This is an exciting opportunity to not only add to our knowledge of the fundamental biology of atherosclerosis, but also to identify regulatory factors that can be manipulated to accelerate regression in patients at risk for coronary artery disease.